AJP - Endocrinology and Metabolism, Vol 271, Issue 1 E113-E122, Copyright © 1996 by American Physiological Society

ARTICLES

Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure

N. D. Vaziri, X. J. Zhou, F. Naqvi, J. Smith, F. Oveisi, Z. Q. Wang and R. E. Purdy
Department of Medicine, University of California, Irvine 92717, USA.

We studied the mechanism of erythropoietin (EPO)-induced hypertension (HTN) in rats with chronic renal failure (CRF). After partial nephrectomy, rats were randomized into four groups. Group A received EPO, 150 U/kg, two times weekly for 6 wk to prevent anemia; group B received placebo injections and became anemic; group C received EPO but was kept anemic by dietary iron deficiency; and group D received placebo and regular transfusions to match hematocrit (Hct) in group A. Blood pressure (BP), Hct, platelet cytosolic calcium ([Ca2+]i) and magnesium concentration, and pressor and vasodilatory responses were determined. By design, Hct in groups A and D were comparable and significantly greater (P < 0.01) than in groups B and C. Despite divergent Hct values, the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy. EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals. EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization, angiotensin II or alpha 1-agonist, methoxamine in vitro, or the pressor response to angiotensin II in vivo. However, EPO therapy impaired the hypotensive response to nitric oxide (NO) donors, sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine, and reversed the CRF-induced upregulation of guanosine 3',5'-cyclic monophosphate production by thoracic aorta in vitro. Thus EPO-induced HTN in CRF rats is Hct independent and is associated with and perhaps causally related to increased basal and stimulated [Ca2+]i and impaired vasodilatory response to NO.

This article has been cited by other articles:

				K. E. Jie, M. C. Verhaar, M.-J. M. Cramer, K. van der Putten, C. A. J. M. Gaillard, P. A. Doevendans, H. A. Koomans, J. A. Joles, and B. Braam Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors Am J Physiol Renal Physiol, November 1, 2006; 291(5): F932 - F944. [Abstract] [Full Text] [PDF]

				A. V. R. Santhanam, L. A. Smith, K. A. Nath, and Z. S. Katusic In vivo stimulatory effect of erythropoietin on endothelial nitric oxide synthase in cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H781 - H786. [Abstract] [Full Text] [PDF]

				J. W. Fisher Erythropoietin: Physiology and Pharmacology Update Experimental Biology and Medicine, January 1, 2003; 228(1): 1 - 14. [Abstract] [Full Text] [PDF]

				B. R. Walker, T. C. Resta, and L. D. Nelin Nitric oxide-dependent pulmonary vasodilation in polycythemic rats Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2382 - H2389. [Abstract] [Full Text] [PDF]

				J. A. Whitworth, G. J. Mangos, and J. J. Kelly Cushing, Cortisol, and Cardiovascular Disease Hypertension, November 1, 2000; 36(5): 912 - 916. [Abstract] [Full Text] [PDF]

				A. BESARAB, S. FRINAK, and J. YEE An Indistinct Balance: The Safety and Efficacy of Parenteral IronTherapy J. Am. Soc. Nephrol., September 1, 1999; 10(9): 2029 - 2043. [Full Text]

				E. BROCHU, S. LACASSE-M, R. LARIVIÈRE, I. KINGMA, J. H. GROSE, and M. LEBEL Differential Effects of Endothelin-1 Antagonists on Erythropoietin-Induced Hypertension in Renal Failure J. Am. Soc. Nephrol., July 1, 1999; 10(7): 1440 - 1446. [Abstract] [Full Text]

				X. Q. Wang and N. D. Vaziri Erythropoietin Depresses Nitric Oxide Synthase Expression by Human Endothelial Cells Hypertension, March 1, 1999; 33(3): 894 - 899. [Abstract] [Full Text] [PDF]

				N. D. Vaziri, Z. Ni, X. Q. Wang, F. Oveisi, and X. J. Zhou Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH Am J Physiol Renal Physiol, April 1, 1998; 274(4): F642 - F649. [Abstract] [Full Text] [PDF]